CN101328167A - Preparation of losartan - Google Patents

Preparation of losartan Download PDF

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CN101328167A
CN101328167A CNA2008101172156A CN200810117215A CN101328167A CN 101328167 A CN101328167 A CN 101328167A CN A2008101172156 A CNA2008101172156 A CN A2008101172156A CN 200810117215 A CN200810117215 A CN 200810117215A CN 101328167 A CN101328167 A CN 101328167A
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preparation
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butyl
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CN101328167B (en
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闫启强
谢苏豪
祁伟
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China Resources Saike Pharmaceutical Co Ltd
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SAIKE PHARMACEUTICAL CO Ltd BEIJING
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a method for preparing losartan. The method comprises the following steps of: removing a protective group of triphenylmethyl from 2-butyl-4-chloro-5-formyl-l-[(2'-(1-triphenylmethyl-tetrazole-5-yl)-biphenyl-4-)methyl] imidazole in the presence of a strong acid to give an intermediate of 2-butyl-4-chloro-5-formyl-1-[(2'-(1-H-tetrazole-5-)-biphenyl-4-)methyl] imidazole; producing 2-butyl-4-chloro-5-(hydroxymethyl)-1[(2'-(1-H-tetrazole-5-yl)-biphenyl-4-) methyl] imidazole in the presence of a reducer.

Description

A kind of preparation method of losartan
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the new preparation process of LOSARTAN POTASSIUM important intermediate losartan.
Background technology
LOSARTAN POTASSIUM (losatan), the methyl of chemistry 2-butyl by name-4-chloro-5-(methylol)-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles.Its structure is seen structural formula II, LOSARTAN POTASSIUM is first husky smooth class antihypertensive drug, suppress the AT acceptor by selectivity, block RAS and play the effect of control blood pressure, it is the non-peptide class angiotensin II receptor antagonists of first listing, pharmacology and clinical trial all show, LOSARTAN POTASSIUM have action range, hypotensive effect significantly, take medicine conveniently, to advantages such as the renal function influence are little.At present more to the Study on Preparation of LOSARTAN POTASSIUM and intermediate losartan thereof, but sum up, mainly contain following three kinds:
The one, coupling method is represented patent US5130439 and EP1777224, and reaction process is as follows
Figure A20081011721500031
The 2nd, adopt 2-butyl-4-chloro-5-hydroxy methylimidazole and 2 '-cyano group-4-bromomethylbiphenyl to carry out the azane glycosylation reaction, become tetrazole to obtain losartan with sodiumazide again, reaction equation is as follows
Representing patent is WO2007020654, WO2007026375 and CN1915990
The 3rd, adopt 2-butyl-4-chloro-5-hydroxy methylimidazole and 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium to carry out the azane glycosylation reaction; the deprotection base that reduces then obtains losartan; represent patent US5130439, EP0253310, reaction equation is as follows
Figure A20081011721500042
Above method operation is loaded down with trivial details, and step is more, and yield is not high, and purity is relatively poor.
The inventor finds the method for a new synthetic losartan through experimental study, compares with existing method, and method of the present invention has simple to operate, and product is easily separated, product quality height, the characteristics that yield is high.
Summary of the invention
The invention provides a kind of preparation method of losartan; it is characterized in that; may further comprise the steps: step 1; in solvent with the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-trityl-tetrazolium-5-yl)-biphenyl-4-)] imidazoles detritylation protecting group under the strong acid effect; form the methyl of intermediate 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles; step 2; in solvent with the methyl of intermediate 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles under the effect of reductive agent, make losartan.
Solvent described in the step 1 is selected from the alcohol of C1-C4, acetone, tetrahydrofuran (THF), dioxane, N, dinethylformamide, preferred tetrahydrofuran (THF) and methyl alcohol.
Strong acid is selected from hydrochloric acid described in the step 1, sulfuric acid, phosphoric acid, preferred hydrochloric acid.
Reductive agent described in the step 2 is a hydroborate, as: POTASSIUM BOROHYDRIDE or sodium borohydride, preferred POTASSIUM BOROHYDRIDE.
Solvent described in the step 2 is the alcohol of C1-C4, particular methanol.
Chemical equation of the present invention is as follows:
Figure A20081011721500051
The present invention specifically can adopt following steps:
(1) methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-trityl-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula IV) synthetic
2-butyl-4-chloro-5-hydroxy methylimidazole and 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium carries out the azane glycosylation reaction by (1: 1 mol ratio) in DMF, salt of wormwood is as alkali, reactant and alkali (mole) ratio is 1: 1～10, preferred 1: 1,24～36 hours reaction times, preferred 24 hours, the temperature of reaction room temperature was to refluxing preferred room temperature.Reaction finishes, and reaction solution is poured in the water, obtains crude product, and crude product need not purified, and directly carries out next step reaction.
(2) methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
At ion solvent (acetone; tetrahydrofuran (THF), dioxane, N; dinethylformamide) or in the alcoholic solvent (alcohol of C1-C4); under 20-100 ℃, with the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-trityl-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula IV) and strong acid (hydrochloric acid, sulfuric acid, phosphoric acid) aqueous solution, wherein the concentration of strong acid is by 1～10N; preferred 3N; the mol ratio of imidazoles and acid 1: 2～1: 10, preferred 1: 3, reaction times 5-24 hour.
(3) methyl of 2-butyl-4-chloro-5-methylol-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II) synthetic
In alcoholic solvent (alcohol of C1-C4); under 20-100 ℃; with the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) is raw material; slowly add hydroborate; wherein reactant and reductive agent mol ratio 1: 0.5～3; preferred 1: 1, reaction times 5-24 hour, preferred 5 hours.
Method of the present invention has simple to operate, and product is easily separated, product quality height, the characteristics that yield is high.
Embodiment:
Following example should not be considered as it restriction to this patent just for the present invention is described
The methyl of embodiment 1:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-trityl-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula IV) synthetic
In the 1L there-necked flask; add 33.5g (0.179mol) 2-butyl-4-chloro-5-hydroxy methylimidazole; 100g (0.179mol) 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium; 300mlDMF; salt of wormwood 47g (0.340mol) is as alkali; reaction was at room temperature reacted 24 hours; reaction finishes; reaction solution is poured in the 600ml water; suction filtration obtains white solid; solid is washed with 100ml; obtain the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-trityl-tetrazolium-5-yl)-biphenyl-4-)] the imidazoles crude product; crude product need not handled, and directly carries out next step reaction, yield 89%.
1HNMR((CDCl3)：0.85(t，3H)，1.23-1.32(sextet，2H)，1.60-1.68(m，2H)，2.50(t，2H)，5.45(s，2H)，6.83(d，2H)，6.91-6.93(m，6H)，7.10(d，2H)，7.20-7.50(m，12H)，7.90-7.95(d，1H)，9.74(s，1H)
The methyl of embodiment 2:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
82g (0.123mol) 2-butyl-4-chloro-5-formyl radical-1-[2 '-(xenyl-4-of 1-trityl-tetrazole base-5-)] Methylimidazole; methyl alcohol 420ml; stir; add 3.4N HCl40ml (0.136mol) in then in 10min; stir under the room temperature and spend the night, add 10N NaOH, be adjusted to pH=13; evaporate to dryness ethanol (420mL) adds the 206mL deionized water.Water layer is washed twice with 2 * 100ml toluene; the water layer of telling slowly splashes into 3.4N hydrochloric acid to pH=3.0, adds the 200ml methylene dichloride and stirs 1 hour; leave standstill separatory; organic layer adds dried over mgso, removes solvent under reduced pressure, obtains crude product; crude product uses column chromatography; ethyl acetate: sherwood oil (volume ratio) 3: 1 is as eluent, obtains the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] the pure product of imidazoles, yield 70%.
1HNMR((CDCl3)：0.84(t，3H)，1.22-1.34(sextet，2H)，1.56-1.64(m，2H)，2.58(t，2H)，5.5(s，2H)，6.94(d，2H)，7.1(d，2H)，7.48(t，1H)，7.48(t，1H)，7.57(t，1H)，7.86(d，1H)，9.6(s，1H)
The methyl of embodiment 3:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
Other condition is constant, and solvent is changed to tetrahydrofuran (THF) by methyl alcohol, yield 35%
The methyl of embodiment 4:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
Other condition is constant, and solvent is changed to DMF by methyl alcohol, yield 60%
The methyl of embodiment 5:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
Other condition is constant, and strong acid is changed to sulfuric acid by hydrochloric acid, yield 75%
The methyl of embodiment 6:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
Other condition is constant, and strong acid is changed to phosphoric acid by hydrochloric acid, yield 72%
The methyl of embodiment 7:2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II I) synthetic
Other condition is constant, and solvent is changed to DMF by methyl alcohol, and strong acid is changed to phosphoric acid by hydrochloric acid, yield 40%
The methyl of embodiment 8:2-butyl-4-chloro-5-methylol-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles (structural formula II) synthetic
With the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles 42g (0.1mol) is dissolved in the 200ml methyl alcohol; slowly adding POTASSIUM BOROHYDRIDE 5.4g (0.1mol) reaction at room temperature reacted 10 hours; solvent evaporated; crude product is recrystallization in toluene, yield 80%.
1HNMR(CDCl3)：0.9(t，3H)，1.2-1.4(m，2H)，1.5-1.7(m，2H)，2.6(t，2H)，4.5(s，2H)，5.2(s，2H)，6.95(d，2H)，7.15(d，2H)，7.35-7.55(m，3H)，7.80-7.90(m，1H).

Claims (10)

1; a kind of preparation method of losartan; it is characterized in that; may further comprise the steps: step 1; in solvent with the methyl of 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-trityl-tetrazolium-5-yl)-biphenyl-4-)] imidazoles detritylation protecting group under the strong acid effect; form the methyl of intermediate 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles; step 2; in solvent with the methyl of intermediate 2-butyl-4-chloro-5-formyl radical-1-[[(2 '-(1-H-tetrazolium-5-yl)-biphenyl-4-)] imidazoles under the effect of reductive agent, make losartan.
2. according to the preparation method of claim 1, it is characterized in that solvent described in the step 1 is selected from the alcohol of C1-C4, acetone, tetrahydrofuran (THF), dioxane, N, dinethylformamide.
3. according to the preparation method of claim 2, it is characterized in that described solvent is a tetrahydrofuran (THF).
4. according to the preparation method of claim 3, it is characterized in that described solvent is a methyl alcohol.
5. according to the preparation method of claim 1, it is characterized in that strong acid is selected from hydrochloric acid described in the step 1, sulfuric acid, phosphoric acid.
6. according to the preparation method of claim 1, it is characterized in that reductive agent described in the step 2 is a hydroborate.
7. according to the preparation method of claim 6, it is characterized in that described reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride.
8. according to the preparation method of claim 1, it is characterized in that the alcohol of the 1-C4 of solvent C described in the step 2.
9. preparation method according to Claim 8 is characterized in that, described solvent methanol.
10. according to the preparation method of claim 1, it is characterized in that solvent described in the step 1 is a methyl alcohol, described strong acid is hydrochloric acid, and solvent described in the step 2 is a methyl alcohol, and described reductive agent is a POTASSIUM BOROHYDRIDE.
CN2008101172156A 2008-07-25 2008-07-25 Preparation of losartan Active CN101328167B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114605393A (en) * 2022-03-17 2022-06-10 浙江工业大学 Method for preparing losartan by micro-channel continuous flow
CN115583940A (en) * 2021-07-05 2023-01-10 润都制药(荆门)有限公司 Method for preparing losartan potassium key intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130439A (en) * 1991-11-18 1992-07-14 Lo Young S Tetrazolylphenylboronic acid intermediates for the synthesis of AII receptor antagonists

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115583940A (en) * 2021-07-05 2023-01-10 润都制药(荆门)有限公司 Method for preparing losartan potassium key intermediate
CN114605393A (en) * 2022-03-17 2022-06-10 浙江工业大学 Method for preparing losartan by micro-channel continuous flow

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Owner name: HUARUN SAIKE PHARMACEUTICAL CO., LTD.

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Address after: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101

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